Indications and Efficacy of DMTs*

EFFICIENCY COMPARISON

33%

53%

RRMS

SPMS

At the follow-up of 33.6 months
(MIST, Phase III, Randomized, n=55)

At the follow-up of 48 months
(Mitoxantrone, ASTIMS, n=12)

INTERNATIONAL EXPERIENCE

SURVIVAL
TIME

RELAPSE free

EFFECTIVENESS
OF
DISEASE MODIFIED THERAPY

PROGRESSIVE free

94%

87%

RRMS

SPMS

At the follow-up of 36 months
(AHSCT RUSSIA, n=258)

At the follow-up of 36 months
(AHSCT RUSSIA, n=160)

Pirogov National Center Experience

SURVIVAL
TIME

RELAPSE free

EFFECTIVENESS
OF
HDIT with AHSCT

PROGRESSIVE free

Our experience

Effectiveness of HDIT with AHSCT at the follow-up

NNEDA under different treatment strategies in patients with RRMS
Proportion of patients maintaining no evidence of disease activity (NEDA) status over time under different treatment strategies.

Points connected by a line represent longitudinal observations in the same study

CLIMB = Harvard Comprehensive Longitudinal Investigation of Multiple Sclerosis (CLIMB) study
DMT = Drug-Modifying Therapy
HSCT = Hematopoietic Stem Cell Transplantation
MIST = Multiple Sclerosis International Stem Cell Transplant Trial

(Copyright permission from: Burt RK, Tappenden P, Han X, Quigley K, Arnautovic I, Sharrack B, Snowden JA, Hartung D. Health economics and patient outcomes of hematopoietic stem cell transplantation versus disease-modifying therapies for relapsing-remitting multiple sclerosis in the United States of America. Mult Scler Relat Disord. 2020;45:102404.)

Autologous HSCT for Relapsing-Remitting Multiple Sclerosis

Three examples of different myeloablative BEAM/ATG (carmustine (BCNU), etoposide (ETP), cytosine arabinoside (Ara-C), melphalan/anti-thymocyte globulin) conditioning regimens for relapsing-remitting multiple sclerosis.

Refer to details in each hematopoietic stem cell transplantation publication, as these are 3 examples and not all the variations in BEAM/ATG and G-CSF dosing strategies.

(A) BEAM/ATG over 7 days
(B) BEAM/ATG over 6 days
(C) less intense mini-BEAM

ATGAM = anti thymocyte gamma globulin (equine origin)
rATG = rabbit origin anti-thymocyte globulin
G-CSF = granulocyte colony stimulating factor
HSC = hematopoietic stem cell.

Common non-myeloablative regimens for RRMS

A - cyclophosphamide/antithymocyte globulin
B - cyclophosphamide/rituximab (verbal communication Dr. Federenko, Moscow, Russia)
C - split dose cyclophosphamide/ rituximab

G-CSF = granulocyte colony-stimulating factor,
HSC = hematopoietic stem cell,
rATG = rabbit anti-thymocyte globulin.

Uppsala (Uppsala, Sweden) and the other from Northwestern University (Chicago, US).
Both studies demonstrated dramatic improvements in neurologic disability of a magnitude that had never previously been reported in clinical trials with DMTs.

Since then several studies of HSCT performed predominately or solely for RRMS have been published with similar results (Table 41.1).

To better understand the profound effect of HSCT for MS, the data were collected before some of the highly active DMTs were licensed, and being a real world setting, a percentage of patients could have been off treatment for variable periods of time.

In comparison, after HSCT for RRMS, NEDA is roughly 70-90% at 2 years and 68-80% at 5 years

NEDA, while a useful clinical endpoint, does not capture improvement in neurologic disability that is most often measured

Indications and Efficacy
of Disease-Modifying Therapies and Supportive Care of Multiple Sclerosis

Indications and Efficacy of DMTs* - International Experience

Avenox;INFβ-1a Biogen 1996 30mcg IM, QW;Relapsing forms of MS to slow accumulation of physical disability and decrease frequency of clinical exacerbations, CIS with MRI features consistent with MS;ARR reduction: 18% 0.56 relative rate of developing secondary relapse from placebo. Disability progression: 37% relative risk reduction in 24-week CDP;50% reduction in number of Gd+ lesions 57% reduction of new or newly enlarging T2 lesions Plegridy;INFβ-1a Biogen 2014 125mcg SC QOW;Relapsing forms of MS;ARR reduction: 36% at 1 year Disability progression: 39% relative risk reduction in 24-week CDP at 1 year;86% reduction of Gd+ lesions 67% reduction of new/enlarging T2 lesions Betaseron;INFβ-1b Bayer 1993 (0,25mg SC QOD);Relapsing forms of MS to reduce frequency of clinical exacerbations, CIS with MRI features consistent with MS;ARR reduction: 31% Disability progression: No effect;Change in MRI lesion area at endpoint -0.9 vs. +0.015 Rebif;INFβ-1a Serono 1996 (22mcg & 44mcg SC TIW);Relapsing forms of MS to decrease frequency of clinical exacerbations and delay the accumulation of physical disability;ARR reduction 29% (22 µg) 32% (44 µg) Disability progression: 22% (22 µg), 31% (44 µg) reduction of CDP;67% (22 mcg) & 78% (44mcg) reduction of active T2 lesions Copaxone;Glatiramer acetate ТЕVA 1996 (20mg SC QD 40mg SC TIW);RRMS for reduction of the frequency of relapses, CIS with MRI features consistent with MS;ARR reduction: 29% (QD) Disability progression: No effect;61% of Gd+ lesions 54% reduction of new/enlarging T2 lesions: 41% reduction of new T1 lesions at 1year Tecfidera;Dimethyl fumarate Biogen 2013 (240mg PO BID);Relapsing forms of MS ;ARR relative reduction: 44% and 53% Disability progression: 21% and 38% relative risk reduction in 24-week CDP;Relative odd.s reduction of Gd+ lesions 74% & 90% 70% & 84% of new and newly enlarging T2 lesions, reduction of 57% & 73% of T1 lesions at two years Aubagio;Teriflunomide Genzyme/Sanofi 2012 (7mg & 14mg PO QD);RRMS;ARR relative reduction 31% (7mg and 14mg) Disability progression: 30-32% relative risk reduction in 12-week CDP;84% (14mg) & 61% (7mg) reduction of Gd+ lesions 72% (14mg) & 36% (7mg) reduction of new T2 lesion volume Gilenya;Fingolimod Novartis 2010 (0.5mg PO QD);Relapsing forms of MS to include CIS, RRMS and active SPMS, in patient 10years of age and older;ARR reduction: 55% vs.placebo, 51% vs.IFNβ-1a QW Disability progression: No effect;82% fewer Gd+ lesions vs.placebo, 60% vs.IFNβ-1a QW 74% fewer new or newly enlarging T2 lesions, 38% vs. IFNβ-1a QW Mayzent;Siponimod Novartis 2019 (2mg PO QD);Relapsing forms of MS to include CIS, RRMS, and active SPMS, in adults;ARR relative reduction: 55% Disability progression: 21% relative risk reduction;T2 lesion volume change from baseline 182 vs 879 on placebo Mavenclad;Cladribine Serono 1993 (Cumulative dose of 3.5mg/kg PO in 2cycles);Relapsing forms of MS to include CIS, RRMS, and aSPMS in adults. Because of its safety profile, its use is generally recommended for patients who have had an inadequate response to, or are unable to tolerate, an alternate drug for the treatment of MS;ARR relative reduction: 58% Disability progression: Time to 3 months disability progression 0.67 hazard ration;Median number of Gd+ lesions 0 vs. 0.33 on placebo Median number of new active T2 lesions: 0 vs. 67 on placebo Tysabri;Natalizumab Biogen 2004 (300mg IVx1 Q 28days);Relapsing forms of MS to include CIS, RRMS, and aSPMS in adults;ARR reduction: 67% Disability progression: 42% risk reduction in 12week & 54% risk reduction in 24week CDP;92% reduction of Gd+ lesions 83% of reduction of new or newly enlarging T2 lesions Ocrevus;Ocrelizumab Genentech 2017 (600mg IVx1 every 6months);Relapsing or primary progressive forms of MS;ARR relative reduction: 46 & 47% vs.IFNβ-1a TIW Disability progression: 40% risk reduction 24week CPD vs.IFNβ-1a TIW (pooled data) 21% risk reduction of 12-week CDP in PPMS;94% & 94% reduction of Gd+ lesions vs.IFNβ-1a TIW 77% & 83% reduction of new or newly enlarging T2 lesions vs.IFNβ-1a TIW Lemtrada;Alemtuzumab Genzyme/Sanofi 2001 12mg IV QD in 2cycles x5days & x3days;Relapsing forms of MS. Its use should be reserved for patients who have had an inadequate response to, or are unable to tolerate, an alternate drug for the treatment of MS;ARR relative reduction: 49% & 55% vs.INFβ-1a TIW Disability progression: 0 & 42% risk reduction in 6months vs.INFβ-1a TIW;Reduced proportion of patient with Gd+ lesions 7% & 9% vs.19% & 23% on INFβ-1a TIW, respectively No difference on T2 lesion volume vs.IINFβ-1a TIW Novantrone;Mitoxantrone Immunex 2000 12mg² IV every 3months over 2years;RRMS, RPMS, SPMS to reduce neurological disability and frequency of relapses;ARR reduction: 66% vs.placebo, 76% on Novantrone plus MP vs.MP Disability progression: EDSS change from baseline -1.3 vs.+2.3 on placebo, EDSS change from baseline -1.1, Novantrone plus MP vs.0.1 on MP alone.;Patients with Gd+ lesions 0 vs. 16 on placebo Patients without Gd+ lesions decreased by 73%, Novantrone plus MP vs. MP Change of T2 lesions: 0.29 vs.1.94 on placeboon placebo Patients without Gd+ lesions decreased by 73%, Novantrone plus MP vs. MP Change of T2 lesions: 0.29 vs.1.94 on placebo